Cutaneous epithelioid haemangiomas show somatic mutations in the mitogen-activated protein kinase pathway.

BACKGROUND: Epithelioid haemangioma (EH) arising from the skin is a benign vascular tumour with marked inflammatory cell infiltration, which exhibits a high tendency to persist and frequently recurs after resection. So far, the underlying pathogenesis is largely elusive. OBJECTIVES: To identify genetic alterations by next-generation sequencing and/or droplet digital polymerase chain reaction (ddPCR) in cutaneous EH. METHODS: DNA and RNA from an EH lesion of an index patient were subjected to whole-genome and RNA sequencing. Multiplex PCR-based panel sequencing of genomic DNA isolated from archival formalin-fixed paraffin-embedded tissue of 18 patients with cutaneous EH was performed. ddPCR was used to confirm mutations. RESULTS: We identified somatic mutations in genes of the mitogen-activated protein kinase (MAPK) pathway (MAP2K1 and KRAS) in cutaneous EH biopsies. By ddPCR we could confirm the recurrent presence of activating, low-frequency mutations affecting MAP2K1. In total, nine out of 18 patients analysed showed activating MAPK pathway mutations, which were mutually exclusive. Comparative analysis of tissue areas enriched for lymphatic infiltrate or aberrant endothelial cells, respectively, revealed an association of these mutations with the presence of endothelial cells. CONCLUSIONS: Taken together, our data suggest that EH shows somatic mutations in genes of the MAPK pathway which might contribute to the formation of this benign tumour.

Cytotoxic benzylidene hydrazides of terephthalic acid and related compounds.

The present investigation involved the synthesis of a number of novel benzylidene hydrazides as candidate cytotoxic agents. The preparation of these compounds from terephthalic acid and isophthalic acid proceeded satisfactorily. However, the reaction of phthalic acid hydrazide with various aryl aldehydes was unsuccessful in general. Some of the unexpected products were identified. The shapes and also the distances between the centers of the aryl rings designated B and C of three representative compounds 1b, 2b and 3b were determined. The compounds designated 1a-e, 2a-e and 3b were screened against human HCT116 and HT29 colon cancer cells as well as human CRL1790 non-malignant colon cells which revealed the tumor-selective toxicity displayed by these compounds.

[3D printing in spinal surgery-Update]. / 3D-Druck in der Wirbelsäulenchirurgie ­ Update.

The technique of 3D printing offers a high potential for further optimization of spinal surgery. This new technology has been published for different areas in the field of spinal surgery, e.g. in preoperative planning, intraoperative use as well as to create patient-specific implants. For example, it has been demonstrated that preoperative 3­dimensional visualization of spinal deformities is helpful in planning procedures. Moreover, insertion of pedicle screws seems to be more accurate when using individualized templates to guide the drill compared to freehand techniques. This review summarizes the current literature dealing with 3D printing in spinal surgery with special consideration of the current applications, the limitations and the future potential.

Light-Induced Renormalization of the Dirac Quasiparticles in the Nodal-Line Semimetal ZrSiSe.

In nodal-line semimetals, linearly dispersing states form Dirac loops in the reciprocal space with a high degree of electron-hole symmetry and a reduced density of states near the Fermi level. The result is reduced electronic screening and enhanced correlations between Dirac quasiparticles. Here we investigate the electronic structure of ZrSiSe, by combining time- and angle-resolved photoelectron spectroscopy with ab initio density functional theory (DFT) complemented by an extended Hubbard model (DFT+U+V) and by time-dependent DFT+U+V. We show that electronic correlations are reduced on an ultrashort timescale by optical excitation of high-energy electrons-hole pairs, which transiently screen the Coulomb interaction. Our findings demonstrate an all-optical method for engineering the band structure of a quantum material.

Evidence of Large Polarons in Photoemission Band Mapping of the Perovskite Semiconductor CsPbBr_{3}.

Lead-halide perovskite (LHP) semiconductors are emergent optoelectronic materials with outstanding transport properties which are not yet fully understood. We find signatures of large polaron formation in the electronic structure of the inorganic LHP CsPbBr_{3} by means of angle-resolved photoelectron spectroscopy. The experimental valence band dispersion shows a hole effective mass of 0.26±0.02 m_{e}, 50% heavier than the bare mass m_{0}=0.17 m_{e} predicted by density functional theory. Calculations of the electron-phonon coupling indicate that phonon dressing of the carriers mainly occurs via distortions of the Pb-Br bond with a Fröhlich coupling parameter α=1.81. A good agreement with our experimental data is obtained within the Feynman polaron model, validating a viable theoretical method to predict the carrier effective mass of LHPs ab initio.

Radial Spin Texture of the Weyl Fermions in Chiral Tellurium.

Trigonal tellurium, a small-gap semiconductor with pronounced magneto-electric and magneto-optical responses, is among the simplest realizations of a chiral crystal. We have studied by spin- and angle-resolved photoelectron spectroscopy its unconventional electronic structure and unique spin texture. We identify Kramers-Weyl, composite, and accordionlike Weyl fermions, so far only predicted by theory, and show that the spin polarization is parallel to the wave vector along the lines in k space connecting high-symmetry points. Our results clarify the symmetries that enforce such spin texture in a chiral crystal, thus bringing new insight in the formation of a spin vectorial field more complex than the previously proposed hedgehog configuration. Our findings thus pave the way to a classification scheme for these exotic spin textures and their search in chiral crystals.

Real-life long-term effectiveness of fingolimod in Swiss patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In 2011, fingolimod was approved in Switzerland for the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real-life Swiss setting, in which patients can receive fingolimod as both first- and second-line treatment for RRMS. METHODS: This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult patients with RRMS who had received treatment with fingolimod were analyzed. RESULTS: Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients who were free from any clinical disease activity, i.e. without relapses and disability progression, was 72.1%. A total of 28.5% of patients had been RRMS treatment-naïve prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. CONCLUSION: In this Swiss cohort of naïve and pre-treated subjects with RRMS, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of previous treatment.

G Protein-Coupled Receptor Signaling Networks from a Systems Perspective.

The signal-transduction network of a mammalian cell integrates internal and external cues to initiate adaptive responses. Among the cell-surface receptors are the G protein-coupled receptors (GPCRs), which have remarkable signal-integrating capabilities. Binding of extracellular signals stabilizes intracellular-domain conformations that selectively activate intracellular proteins. Hereby, multiple signaling routes are activated simultaneously to degrees that are signal-combination dependent. Systems-biology studies indicate that signaling networks have emergent processing capabilities that go far beyond those of single proteins. Such networks are spatiotemporally organized and capable of gradual, oscillatory, all-or-none, and subpopulation-generating responses. Protein-protein interactions, generating feedback and feedforward circuitry, are generally required for these spatiotemporal phenomena. Understanding of information processing by signaling networks therefore requires network theories in addition to biochemical and biophysical concepts. Here we review some of the key signaling systems behaviors that have been discovered recurrently across signaling networks. We emphasize the role of GPCRs, so far underappreciated receptors in systems-biology research.

CD68 expression is a discriminative feature of indolent cutaneous CD8-positive lymphoid proliferation and distinguishes this lymphoma subtype from other CD8-positive cutaneous lymphomas.

BACKGROUND: Indolent cutaneous CD8+ lymphoid proliferation is a recently described rare entity among cutaneous T-cell lymphomas that typically presents with solitary skin lesions at acral sites. Separation from otherwise aggressive T-cell lymphomas bearing a cytotoxic CD8+ phenotype is fundamental to avoid unnecessary harmful treatment. However, up to now, no reliable discriminative marker has been identified. OBJECTIVES: Motivated by these diagnostic quandaries, we have analyzed a large series of archived formalin-fixed paraffin-embedded (FFPE) specimens of atypical CD8+ cutaneous infiltrates with clear-cut diagnosis and clinical follow-up (n = 44) including five cases of indolent CD8+ lymphoid proliferation by using immunohistochemistry with the aim of obtaining markers predictive of subtype assignment. RESULTS: We identified exclusive expression of CD68 by lymphoma cells within the subgroup of indolent CD8+ lymphoid proliferation (5/5 cases). Specific CD68 expression in this entity was confirmed by the application of several monoclonal antibodies (KP1, PG-M1, KiM1P) against the CD68 molecule available for FFPE tissue. In contrast, none of the infiltrates of the other CD8+ cutaneous lymphoma entities stained positive for CD68 (0/39). CONCLUSIONS: Based on these observations, we suggest CD68 as a new discriminative marker which is helpful in distinguishing indolent CD8+ lymphoid proliferation from other CD8+ cutaneous lymphomas in ambiguous cases.

Colloidal Nanoparticle Interaction Transition during Solvent Evaporation Investigated by in-Situ Small-Angle X-ray Scattering.

In-situ scanning small-angle X-ray scattering (SAXS) experiments have been performed to probe the drying of a single suspended droplet of silica colloids. It has been demonstrated that the formation of a nanoparticle shell during drying can be confirmed just by measuring the temporal evolution of the spatial transmission profile across the drying droplet. The shrinkage of the droplet stops once the shell is formed. The temporal dependence of the shell thickness and droplet radius has been estimated by quantitative analysis of the functionality of the transmission profiles. It is revealed that the position of the correlation peak originating from interactions between silica nanoparticles evolves linearly during the initial stage of drying and exhibits sigmoidal growth behavior in later stages. The interaction between colloidal particles in different drying stages has been investigated. We provide experimental confirmation of the transition from repulsive interaction to a capillary-driven short-range attraction during shell formation. The present work demonstrates that in-situ scanning SAXS on a suspended droplet is an invaluable technique for monitoring the dynamic self-organization of colloids as it probes the drying of complex fluids without the interference of a substrate.

Probing evaporation induced assembly across a drying colloidal droplet using in situ small-angle X-ray scattering at the synchrotron source.

Colloidal particles in a tiny drying droplet are forced to assemble due to attractive capillary forces. Jamming of the particles throughout the droplet remains either isotropic or anisotropic depending upon the drying kinetics and the physicochemical environment. In this work, we explore the dynamical evolution of such an assembly process across a single evaporative droplet by in situ scanning small-angle scattering using a micro-focused X-ray beam at the synchrotron source. A methodology has been elucidated to differentiate quantitatively between the isotropic and the anisotropic jamming process. Switching of jamming behaviour depending on the initial particle volume fraction in the droplet has been demonstrated. Three distinct stages of assembly, associated with droplet shrinkage, have been revealed even during isotropic jamming. This is in contrast to the drying of a pure liquid droplet under diffusion limited evaporation. It has been established that such in situ scattering measurements can also be used to estimate the temporal evolutions of the viscosity of a drying suspension as well as the diffusivity of nanoparticles in a droplet.

Psychological distress and adjustment to disease in patients before and after radical prostatectomy. Results of a prospective multi-centre study.

The aim of this prospective multi-centre study was to evaluate the level of psychological distress (PD) and adjustment to disease in patients who underwent radical prostatectomy. Furthermore, the impact of urinary incontinence and erectile dysfunction on PD was assessed. Anxiety, depression and PD were evaluated using the Hospital Anxiety and Depression Scale in 329 prostate cancer patients before surgery as well as 3, 6 and 12 months after surgery. These results were compared with those of a male German general population reference group. Adjustment to disease was assessed using the Perceived Adjustment to Chronic Illness Scale. Patients reported low levels of PD at all points of assessment similar to population norms of age-matched German men. Persistent PD was seen in about 8% of the patients and 20% had PD at least two of the measurement points. Relevant predictors for PD after surgery were urinary symptoms and baseline PD. Adjustment to disease was highest before surgery and had significantly reduced at 3 and 6 months after surgery. In general, men are resilient to the experience of localised prostate cancer and adjust well psychologically after surgery. However, between 8% and 20% of patients could possibly benefit from mental health support.

[Osteoporotic vertebral fractures of the thoracic and lumbar spine]. / Osteoporotische Wirbelkörperfrakturen der Brust- und Lendenwirbelsäule.

The frequency of osteoporotic vertebral fractures in the clinical routine is increasing due to the demographic change. They are the most frequent fractures associated with osteoporosis and affect an especially morbid and vulnerable group of patients. These fractures often occur after minor trauma or spontaneously. Pain is the predominant symptom, whereas mechanical stability is mostly sufficient, in comparison to vertebral fractures after high-energy trauma, and is not a predominant indication for surgery. These fractures can be described using the classification for fractures associated with osteoporosis and the corresponding treatment recommendations are guided by them. Besides the specific treatment of osteoporotic vertebral fractures, a holistic treatment of patients taking pre-existing comorbidities into consideration is decisive. A mobilization as quickly as possible and treatment of the underlying osteoporosis are important to prevent further fractures.

Excitation of coherent phonons in the one-dimensional Bi(114) surface.

We present time-resolved photoemission experiments from a peculiar bismuth surface, Bi(114). The strong one-dimensional character of this surface is reflected in the Fermi surface, which consists of spin-polarized straight lines. Our results show that the depletion of the surface state and the population of the bulk conduction band after the initial optical excitation persist for very long times. The disequilibrium within the hot electron gas along with strong electron-phonon coupling cause a displacive excitation of coherent phonons, which in turn are reflected in coherent modulations of the electronic states. Beside the well-known A(1g) bulk phonon mode at 2.76 THz, the time-resolved photoelectron spectra reveal a second mode at 0.72 THz which can be attributed to an optical surface phonon mode along the atomic rows of the Bi(114) surface.

In situ X-ray study of the structural evolution of gold nano-domains by spray deposition on thin conductive P3HT films.

Gold (Au) nanoparticles are deposited from aqueous solution onto one of the most used conductive polymers, namely poly(3-hexylthiophene) (P3HT), using airbrush deposition. We report on the structure formation and packing of the Au nanoparticles after a 5 s spray cycle. In situ grazing incidence small-angle X-ray scattering (GISAXS) measurements with 20 ms time resolution allow a real-time observation of the emergence and evolution of the microstructure during a spray cycle and subsequent solvent evaporation. The results reveal multistage nanoscale ordering of the Au nanoparticles during the spray cycle. Further ex situ atomic force microscopy measurements of the sprayed films showed the formation of Au monolayer islands on top of the polymer film. Our study suggests that the solvent-substrate interaction as well as solvent evaporation kinetics are important factors that need to be taken into consideration in order to grow a compact uniform monolayer film for the fabrication of ultrathin films using airbrush deposition.

The structure of suspended graphene sheets.

The recent discovery of graphene has sparked much interest, thus far focused on the peculiar electronic structure of this material, in which charge carriers mimic massless relativistic particles. However, the physical structure of graphene--a single layer of carbon atoms densely packed in a honeycomb crystal lattice--is also puzzling. On the one hand, graphene appears to be a strictly two-dimensional material, exhibiting such a high crystal quality that electrons can travel submicrometre distances without scattering. On the other hand, perfect two-dimensional crystals cannot exist in the free state, according to both theory and experiment. This incompatibility can be avoided by arguing that all the graphene structures studied so far were an integral part of larger three-dimensional structures, either supported by a bulk substrate or embedded in a three-dimensional matrix. Here we report on individual graphene sheets freely suspended on a microfabricated scaffold in vacuum or air. These membranes are only one atom thick, yet they still display long-range crystalline order. However, our studies by transmission electron microscopy also reveal that these suspended graphene sheets are not perfectly flat: they exhibit intrinsic microscopic roughening such that the surface normal varies by several degrees and out-of-plane deformations reach 1 nm. The atomically thin single-crystal membranes offer ample scope for fundamental research and new technologies, whereas the observed corrugations in the third dimension may provide subtle reasons for the stability of two-dimensional crystals.

Predation by carabid beetles on the invasive slug Arion vulgaris in an agricultural semi-field experiment.

Arion vulgaris Moquin-Tandon 1855 is one of the most important invasive species in Europe, affecting both biodiversity and agriculture. The species is spreading in many parts of Europe, inflicting severe damage to horticultural plants and cultivated crops partly due to a lack of satisfactory and effective management solutions. Molluscicides have traditionally been used to manage slug densities, although the effects are variable and some have severe side-effects on other biota. Thus, there is a need to explore potential alternatives such as biological control. The nematode Phasmarhabditis hermaphrodita is the only biological agent that has been applied commercially so far. However, other biological control agents such as carabid beetles have also been found to be promising. In addition, some carabid species have been shown to feed on A. vulgaris in the field as well as in the laboratory. Two species in particular have been found to be important predators of A. vulgaris, and these species are also common in agricultural environments: Pterostichus melanarius and Carabus nemoralis. This study is the first to use semi-field experiments in a strawberry field, manipulating densities, to investigate how P. melanarius and C. nemoralis affect densities of A. vulgaris eggs and juveniles, respectively. Gut contents of C. nemoralis were analysed using multiplex PCR methods to detect DNA of juvenile slugs. Results show that both P. melanarius and C. nemoralis significantly affect densities of slug eggs and juvenile slugs under semi-field conditions and that C. nemoralis seems to prefer slugs smaller than one gram. Carabus nemoralis seems to be especially promising in reducing densities of A. vulgaris, and future studies should investigate the potential of using this species as a biological control agent.

Urinary retention: benefit of gradual bladder decompression - myth or truth? A randomized controlled trial.

INTRODUCTION: Urinary retention is a common emergency requiring immediate catheterization. Gradual decompression (GD) of the extended bladder is believed to minimize the risk of complications such as bleeding or circulatory collapse, but to date it has not been compared with rapid decompression (RD) in controlled trials. MATERIALS AND METHODS: Male patients presenting with urinary retention (n = 294) were randomized to rapid or gradual catheterization. For the latter, the transurethral catheter was clamped for 5 min after every 200-ml outflow until the bladder was completely empty. Patients were monitored for at least 30 min thereafter with regular checks of vital signs and presence of macroscopic hematuria. RESULTS: Of 294 patients, 142 (48.3%) were randomized to the GD and 152 (51.7%) to the RD group. Both groups showed no statistically significant difference with regard to age, anticoagulation treatment, catheter size and material, or volume retained. Hematuria occurred in 16 (11.3%) of the GD and 16 (10.5%) of the RD group; 6 patients in the former and 4 in the latter required further treatment. No circulatory collapse occurred. We noted a decrease in the previously raised blood pressure and heart rate in both groups, although without clinical significance. CONCLUSION: In this first randomized trial, no statistically significant difference was noted between gradual and rapid emptying of the bladder for urinary retention. Gradual emptying did not reduce the risk of hematuria or circulatory collapse. Therefore, there is no need to prefer gradual over rapid emptying, which is both easy and safe.

Loss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development.

Histone acetyltransferases regulate transcription, but little is known about the role of these enzymes in developmental processes. Gcn5 (encoded by Gcn5l2) and Pcaf, mouse histone acetyltransferases, share similar sequences and enzymatic activities. Both interact with p300 and CBP (encoded by Ep300 and Crebbp, respectively), two other histone acetyltransferases that integrate multiple signalling pathways. Pcaf is thought to participate in many of the cellular processes regulated by p300/CBP (refs 2-8), but the functions of Gcn5 are unknown in mammalian cells. Here we show that the gene Pcaf is dispensable in mice. In contrast, Gcn5l2-null embryos die during embryogenesis. These embryos develop normally to 7.5 days post coitum (d.p.c.), but their growth is severely retarded by 8.5 d.p.c. and they fail to form dorsal mesoderm lineages, including chordamesoderm and paraxial mesoderm. Differentiation of extra-embryonic and cardiac mesoderm seems to be unaffected. Loss of the dorsal mesoderm lineages is due to a high incidence of apoptosis in the Gcn5l2 mutants that begins before the onset of morphological abnormality. Embryos null for both Gcn5l2 and Pcaf show even more severe defects, indicating that these histone acetyltransferases have overlapping functions during embryogenesis. Our studies are the first to demonstrate that specific acetyltransferases are required for cell survival and mesoderm formation during mammalian development.

Quantitative perfusion and water transport time model from multi b-value diffusion magnetic resonance imaging validated against neutron capture microspheres.

Intravoxel Incoherent Motion (IVIM) is a non-contrast magnetic resonance imaging diffusion-based scan that uses a multitude of b-values to measure various speeds of molecular perfusion and diffusion, sidestepping inaccuracy of arterial input functions or bolus kinetics in quantitative imaging. We test a new method of IVIM quantification and compare our values to reference standard neutron capture microspheres across normocapnia, CO2 induced hypercapnia, and middle cerebral artery occlusion in a controlled animal model. Perfusion quantification in ml/100g/min compared to microsphere perfusion uses the 3D gaussian probability distribution and defined water transport time as when 50% of the molecules remain in the tissue of interest. Perfusion, water transport time, and infarct volume was compared to reference standards. Simulations were studied to suppress non-specific cerebrospinal fluid (CSF). Linear regression analysis of quantitative perfusion returned correlation (slope = .55, intercept = 52.5, $R^2$= .64). Linear regression for water transport time asymmetry in infarcted tissue was excellent (slope = .59, intercept = .3, $R^2$ = .93). Strong linear agreement also was found for infarct volume (slope = 1.01, $R^2$= .79). Simulation of CSF suppression via inversion recovery returned blood signal reduced by 82% from combined T1 and T2 effects. Intra-physiologic state comparison of perfusion shows potential partial volume effects which require further study especially in disease states. The accuracy and sensitivity of IVIM provides evidence that observed signal changes reflect cytotoxic edema and tissue perfusion. Partial volume contamination of CSF may be better removed during post-processing rather than with inversion recovery to avoid artificial loss of blood signal.